Diabetes mellitus is a type of metabolic disorder of carbohydrates, fat and protein due to lack of insulin or insulin resistance and a group of clinical syndromes mainly characterized by chronic hyperglycemia (blood-fasting glucose concentration>130 mg/dL) and glycosuria. Sustained hyperglycemia would cause the occurrence of many complications, such as retinopathy, renal lesions, nervous system lesions and blood vessel complication, in which cardiovascular complications are especially major cause leading to death or disability of diabetes patients, thus controlling the blood glucose level of patient is very important for delaying or blocking the occurrence of complications.
Diabetes type II is one type of common chronic disease mainly characterized by hyperglycemia which occurs accompanying insulin resistance, relative decrease of insulin secretion inside body and increase of liver glyconeogenesis [Exp. Opin. Ther. Patents, 2003, 13(4):99-51].
At present, the drugs for treating diabetes type II mainly include insulin, biguanide such as metformin, sulfonylurea such as glimepiride, a glycosidase inhibitors such as acarbose, repaglinides such as rosiglitazone. But in addition to limited therapeutic effect, all these drugs poss apparent adverse effects.
So, there exists an urgent need to develop a novel, more effective and safer drug for treating diabetes. Many new treating targets are under study in which the results from pharmaceutical study with dipeptidyl peptidase IV (DPP-IV) as target are particularly excellent [medicinal research Review, 2009, 29(1), 125-195].
Glucagon-like peptide-1 (GLP-1) is secreted by pancreatic islet α cells and intestinal L cells which can glucose-dependently increase the secretion of insulin and enhance the biosynthesis of insulin, so the use of GLP-1 to treat diabetes caused great interests of scientists. In addition to enhancing insulin secretion, GLP-1 also has many physiological functions such as facilitating the proliferation of β cells, preventing apoptosis of β cells, inhibiting the production of glucagon and glycogen, controlling appetite, decreasing the speed of gastrointestinal emptying, protecting nerve cells and the like [Trends Endocrinol Metab, 1999, 10(6):229-235]. GLP-1 is a polypeptide containing 30 amino acids, glucose and fat can simulate its release. These properties of GLP-1 make it an ideal diabetic drug. Continuous i.v. drip of GLP-1 can decrease the blood glucose level of patient, even being effective for patients failed by sulfonylurea therapy, but single subcutaneous injection is ineffective, and continuous subcutaneous injection for 6 weeks would give ideal outcomes. The cause of this phenomenon is that the half life of GLP-1 in vivo is only several minutes and GLP-1 could be rapidely degradated by endogenous dipeptidyl peptidase (DPP-IV) and lose its activity of enhancing insulin secretion by cutting N-terminal dipeptide [Expert Opin. Investing. Drugs, 2004, 13(9):1091-1102]. DPP-IV generally distributes in body and is major metabolic enzyme of GLP-1 which plays an important role in regulating activity of GLP-1. So, active compounds which can inhibit DPP-I, i.e., DPPIV inhibitors could enhance the effects of GLP-1 (intestinal glucokinin) and is intend to be a novel therapeutic drug for type 2 diabetes.
In addition, DPP-IV inhibitor also has many functions such as facilitating the proliferation of β cells, preventing apoptosis of β cells, inhibiting the production of glucagon and glycogen, suppressing appetite, not increasing body weight, decreasing the speed of gastrointestinal emptying, protecting nerve cells and the like [Trends Endocrinol Metab, 1999, 10(6):229-235]. So, DPP-IV inhibitor also can be used to treat various diseases associated with dipeptidyl peptidase such as obesity and hyperlipemia [Diabetologia, 2007, 50(6):1148-1155; Regul Pept, 2008, 31(1):108-113].
Existing references and patents disclosed a lot of DPP-IV inhibitors [Current Medicinal Chemistry, 1999, 6, 311-327; Biochemistry 1999, 38, 11597-11603; Expert Opin. Ther. Patents, 2003, 13(4):499-510; Expert Opin. Investing. Drugs, 2005, 15(10):1387-1407]. WO 00/34241 disclosed N-substituted-2-cyanopyrroleidines compounds having DPP-IV inhibiting activity in which adamantine moiety is mon-substituted or simply alkyl-substituted. US 2003/0100563 disclosed β-amino heterocyclic DPP-IV inhibitors for diabetes treatment. WO 03/057666 disclosed cyclopropanated 2-cyanopyrroles DPP-IV inhibitors. US 2004/0171848 disclosed a series of 2-cyanopyrrole compounds containing diphenyl side chain. WO 2005/095381 disclosed a type of 2,4-dioxy-3,4-dihydropyrimidines DPP-IV inhibitors with new structure.
DPP-IV inhibitor Sitagliptin (MK-0431) and Vildagliptin (LAF-237) cameto market in USA and Europe respectively which were used to treat diabetes.

However, among the existing technologies, the inhibiting activity of these compounds against dipeptidyl peptidase is not satisfying and their ability to decrease blood glucose level and HbAIc is lower than that of metformin [Medicinal Research Review, 2009, 29(1), 125-195]. In view of this, there exists an urgent need in the art to develop an inhibitor of dipeptidyl peptidase with higher activity and selectivity in order to treat various diseases associated with dipeptidyl peptidase (DPP-IV).